The overall objective is to elucidate the mechanisms of action of the opiate narcotics and the relationship to the addictive process. Investigations are directed at the most significant aspects at various levels of interaction of the drugs with biologic systems, specifically: the interactions of narcotics with opiate receptors, the nature and properties of the receptors, and their physiologic (as distinct from pharmacologic) role; the proximate biochemical consequences of the narcotic-receptor interaction; the effects of the key biochemical alterations upon the neuronal function in opiate-sensitive neurons; the consequences of specific neuronal change upon the whole organism, as manifested by what we recognize as typical opiate actions; the biochemical and neuronal alterations underlying the states of tolerance and physical dependence. BIBLIOGRAPHIC REFERENCES: Dingledine, R. and Goldstein, A. Effect of synaptic transmission blockade on morphine action in the guinea pig myenteric plexus. J. Pharmacol. Exp. Ther. 196: 97, 1976. Goldstein, A Pryor, G. T., Otis L. S. and Larsen, F. On the role of endogenous opioid peptides: Failure of naloxone to influence shock escape threshold in the rat. Life Sci. 18: 599, 1976.